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https://www.readbyqxmd.com/read/28429084/rs4878104-contributes-to-alzheimer-s-disease-risk-and-regulates-dapk1-gene-expression
#1
Yang Hu, Liang Cheng, Ying Zhang, Weiyang Bai, Wenyang Zhou, Tao Wang, Zhifa Han, Jian Zong, Shuilin Jin, Jun Zhang, Qinghua Jiang, Guiyou Liu
In 2006, a candidate gene study reported death-associated protein kinase 1 (DAPK1) rs4878104 variant to be significantly associated with Alzheimer's disease (AD) risk. However, the following studies showed inconsistent association results. Here, we conducted an updated analysis to investigate the potential association between rs4878104 and AD using a total of 60,751 samples (20,161 AD cases and 40,590 controls). In the pooled population, the results based on the allele and genotype genetic models show that rs4878104 variant is not significantly associated with AD risk...
April 20, 2017: Neurological Sciences
https://www.readbyqxmd.com/read/28426719/transcriptome-of-interstitial-cells-of-cajal-reveals-unique-and-selective-gene-signatures
#2
Moon Young Lee, Se Eun Ha, Chanjae Park, Paul J Park, Robert Fuchs, Lai Wei, Brian G Jorgensen, Doug Redelman, Sean M Ward, Kenton M Sanders, Seungil Ro
Transcriptome-scale data can reveal essential clues into understanding the underlying molecular mechanisms behind specific cellular functions and biological processes. Transcriptomics is a continually growing field of research utilized in biomarker discovery. The transcriptomic profile of interstitial cells of Cajal (ICC), which serve as slow-wave electrical pacemakers for gastrointestinal (GI) smooth muscle, has yet to be uncovered. Using copGFP-labeled ICC mice and flow cytometry, we isolated ICC populations from the murine small intestine and colon and obtained their transcriptomes...
2017: PloS One
https://www.readbyqxmd.com/read/28426203/tyrosine-kinase-activation-and-conformational-flexibility-lessons-from-src-family-tyrosine-kinases
#3
Yilin Meng, Matthew P Pond, Benoît Roux
Protein kinases are enzymes that catalyze the covalent transfer of the γ-phosphate of an adenosine triphosphate (ATP) molecule onto a tyrosine, serine, threonine, or histidine residue in the substrate and thus send a chemical signal to networks of downstream proteins. They are important cellular signaling enzymes that regulate cell growth, proliferation, metabolism, differentiation, and migration. Unregulated protein kinase activity is often associated with a wide range of diseases, therefore making protein kinases major therapeutic targets...
April 20, 2017: Accounts of Chemical Research
https://www.readbyqxmd.com/read/28419164/population-pharmacokinetic-modelling-of-rupatadine-solution-in-6-11-year-olds-and-optimisation-of-the-experimental-design-in-younger-children
#4
Eva Santamaría, Javier Alejandro Estévez, Jordi Riba, Iñaki Izquierdo, Marta Valle
AIMS: To optimise a pharmacokinetic (PK) study design of rupatadine for 2-5 year olds by using a population PK model developed with data from a study in 6-11 year olds. The design optimisation was driven by the need to avoid children's discomfort in the study. METHODS: PK data from 6-11 year olds with allergic rhinitis available from a previous study were used to construct a population PK model which we used in simulations to assess the dose to administer in a study in 2-5 year olds...
2017: PloS One
https://www.readbyqxmd.com/read/28417561/population-pharmacokinetics-of-morphine-in-patients-with-nonalcoholic-steatohepatitis-nash-and-healthy-adults
#5
V Pierre, C K Johnston, B C Ferslew, Klr Brouwer, D Gonzalez
Altered expression and function of transporters in nonalcoholic steatohepatitis (NASH) patients may affect the pharmacokinetics (PK), efficacy, and safety of substrate drugs. A population pharmacokinetic (PopPK) analysis was performed to assess differences in morphine and morphine-3-glucuronide (M3G) disposition in NASH and healthy subjects. A total of 315 serum and 42 urine samples from 21 subjects (14 healthy; 7 NASH) were analyzed using NONMEM. Morphine and M3G PK were described by three- and one-compartment models, respectively...
April 18, 2017: CPT: Pharmacometrics & Systems Pharmacology
https://www.readbyqxmd.com/read/28413519/amp-activated-protein-kinase-mediates-the-effects-of-lipoprotein-associated-phospholipase-a2-on-endothelial-dysfunction-in-atherosclerosis
#6
Li Yang, Hong-Liang Cong, Shu-Feng Wang, Ting Liu
The present study aimed to investigate the effects of lipoprotein-associated phospholipase A2 (Lp-PLA2) on endothelial dysfunction in an in vitro cell model of atherosclerosis, and to determine whether AMP-activated protein kinase (AMPK) mediates the effects of Lp-PLA2 on endothelial dysfunction. A total of 392 patients with coronary artery disease (CAD), including various sub-conditions, were recruited, and the plasma concentrations of Lp-PLA2 were evaluated. In addition, an in vitro model of atherosclerosis was established by exposing human umbilical vein endothelial cells (HUVECs) to oxidized low-density lipoprotein (oxLDL)...
April 2017: Experimental and Therapeutic Medicine
https://www.readbyqxmd.com/read/28410277/use-of-population-pharmacokinetics-and-electronic-health-records-to-assess-piperacillin-tazobactam-safety-in-infants
#7
Sara Salerno, Christoph P Hornik, Michael Cohen-Wolkowiez, P Brian Smith, Lawrence C Ku, Matthew S Kelly, Reese Clark, Daniel Gonzalez
BACKGROUND: Piperacillin, in combination with tazobactam, is frequently used in infants for treating nosocomial infections, although safety data in this population are limited. Electronic health record (EHR) data can be used to evaluate drug safety in infants, but measures of drug exposure are lacking. METHODS: To relate simulated piperacillin exposure with adverse events (AEs) in infants using EHR data, we identified infants discharged from 333 neonatal intensive care units managed by the Pediatrix Medical Group between 1997 and 2012...
April 13, 2017: Pediatric Infectious Disease Journal
https://www.readbyqxmd.com/read/28409203/the-role-of-infection-models-and-pk-pd-modelling-for-optimising-care-of-critically-ill-patients-with-severe-infections
#8
REVIEW
T Tängdén, V Ramos Martín, T W Felton, E I Nielsen, S Marchand, R J Brüggemann, J B Bulitta, M Bassetti, U Theuretzbacher, B T Tsuji, D W Wareham, L E Friberg, J J De Waele, V H Tam, Jason A Roberts
Critically ill patients with severe infections are at high risk of suboptimal antimicrobial dosing. The pharmacokinetics (PK) and pharmacodynamics (PD) of antimicrobials in these patients differ significantly from the patient groups from whose data the conventional dosing regimens were developed. Use of such regimens often results in inadequate antimicrobial concentrations at the site of infection and is associated with poor patient outcomes. In this article, we describe the potential of in vitro and in vivo infection models, clinical pharmacokinetic data and pharmacokinetic/pharmacodynamic models to guide the design of more effective antimicrobial dosing regimens...
April 13, 2017: Intensive Care Medicine
https://www.readbyqxmd.com/read/28408267/population-pharmacokinetics-of-moxifloxacin-cycloserine-p-aminosalicylic-acid-and-kanamycin-for-the-treatment-of-multi-drug-resistant-tuberculosis
#9
Min Jung Chang, Byunghak Jin, Jung-Woo Chae, Hwi-Yeol Yun, Eun Sun Kim, Yeon Joo Lee, Young-Jae Cho, Ho Il Yoon, Choon-Taek Lee, Kyoung Un Park, Junghan Song, Jae-Ho Lee, Jong Sun Park
Control of multi-drug-resistant tuberculosis (MDR-TB) requires extensive, supervised chemotherapy because second-line anti-TB drugs have a narrower therapeutic range than first-line drugs. This study aimed to develop population pharmacokinetic (PK) models for second-line drugs in patients with MDR-TB, evaluate the recommended dosage regimens and, if necessary, suggest new dosage regimens. A prospective, single-centre PK study was performed on second-line anti-TB drugs in patients with MDR-TB. Moxifloxacin, cycloserine, p-aminosalicylic acid (PAS), kanamycin and other second-line drugs were administered to the patients...
April 10, 2017: International Journal of Antimicrobial Agents
https://www.readbyqxmd.com/read/28406633/probing-the-conformationally-excited-states-of-membrane-proteins-via-1-h-detected-mas-solid-state-nmr-spectroscopy
#10
T Gopinath, Sarah E D Nelson, Kailey J Soller, Gianluigi Veglia
Proteins exist in ensembles of conformational states that interconvert on various motional time scales. High-energy states of proteins, often referred to as conformationally excited states, are sparsely populated and have been found to play an essential role in many biological functions. However, detecting these states is quite difficult for conventional structural techniques. Recent progress in solution NMR spectroscopy made it possible to detect conformationally excited states in soluble proteins and characterize them at high resolution...
April 20, 2017: Journal of Physical Chemistry. B
https://www.readbyqxmd.com/read/28406088/population-pharmacokinetics-of-vancomycin-in%C3%A2-chinese-infants%C3%A2
#11
Xiao-Yan Sheng, Chao-Yang Chen, Ling-Yue Ma, Ya-Ou Liu, Ying Zhou, Yi-Min Cui
OBJECTIVE: To determine the pharmacokinetics (PK) of vancomycin in Chinese infant patients using a population pharmacokinetic (PKK) approach in order to provide support for individualized vancomycin therapy. METHOD: The data included 72 sets of steady-state peak and trough serum concentrations from 61 infants (0 - 1 years). PPK analysis was performed using the nonlinear mixed-effects modeling software. Inter- and intraindividual variability was estimated for the clearance and distribution volume of vancomycin...
April 13, 2017: International Journal of Clinical Pharmacology and Therapeutics
https://www.readbyqxmd.com/read/28401480/target-mediated-drug-disposition-pharmacokinetic-pharmacodynamic-model-of-bosentan-and-endothelin-1
#12
Anke-Katrin Volz, Andreas Krause, Walter Emil Haefeli, Jasper Dingemanse, Thorsten Lehr
BACKGROUND AND OBJECTIVES: Bosentan is a competitive antagonist on endothelin receptor A and B (ETA and ETB), displacing the endogenous binding partner endothelin-1 (ET-1) from its binding sites. After administration of escalating single doses of 10-750 mg as an intravenous (i.v.) infusion, bosentan showed dose-dependent pharmacokinetics (PK). The aim of this analysis was to develop a PK model of bosentan after i.v. administration including competitive antagonism with ET-1 and to analyze its influence on blood pressure and heart rate with a combined pharmacokinetic/pharmacodynamic (PK/PD) model...
April 11, 2017: Clinical Pharmacokinetics
https://www.readbyqxmd.com/read/28399643/the-effect-of-pde5-inhibitors-on-bone-and-oxidative-damage-in-ovariectomy-induced-osteoporosis
#13
Hamit H Alp, Zübeyir Huyut, Serkan Yildirim, Yıldıray Başbugan, Levent Ediz, Mehmet R Şekeroğlu
Osteoporosis is a major public health problem associated with many factors, and it affects more than 50% of women over 50 years old. In the current study, our purpose was to investigate the effects of phosphodiestarase-5 inhibitors on osteoporosis via the nitric oxide/3',5'-cyclic guanosine monophosphate/protein kinase G signalling pathway. A total of 50 female albino Wistar rats were separated into five groups. The first group was appointed as the healthy control group with no ovariectomy. All animals in the other groups underwent a bilateral ovariectomy...
January 1, 2017: Experimental Biology and Medicine
https://www.readbyqxmd.com/read/28399040/a-new-enzyme-linked-immunosorbent-assay-elisa-for-a-total-anti-t-lymphocyte-globulin-determination-development-analytical-validation-and-clinical-application
#14
M Montagna, G La Nasa, M E Bernardo, E Piras, M A Avanzini, M Regazzi, F Locatelli
BACKGROUND: Anti-T lymphocyte globulin (ATLG) modulates the alloreactivity of T lymphocytes, reducing the risk of immunological post-transplant complications, in particular rejection and graft-versus-host disease (GvHD), after allogeneic hematopoietic stem cell transplantation (HSCT).We developed and validated a new enzyme-linked immunosorbent assay (ELISA) method to measure serum levels of total ATLG and evaluate the pharmacokinetics (PK) of the drug in children with β-Thalassemia, receiving allogeneic HSCT...
April 7, 2017: Therapeutic Drug Monitoring
https://www.readbyqxmd.com/read/28398628/population-pharmacokinetics-and-target-engagement-of-natalizumab-in-patients-with-multiple-sclerosis
#15
Kumar Kandadi Muralidharan, Geoffrey Kuesters, Tatiana Plavina, Meena Subramanyam, Daniel D Mikol, Sreeja Gopal, Ivan Nestorov
Natalizumab (humanized immunoglobulin G4 antibody targeting alpha-4 integrins) is a highly efficacious treatment for relapsing-remitting multiple sclerosis (RRMS) that has been in clinical use since 2006. However, natalizumab pharmacokinetic (PK) characteristics and concentration alpha-4 integrin saturation relationships have not been well described in the scientific literature. Therefore, clinical data from 11 studies were pooled and analyzed to characterize the PK and pharmacodynamic (PD) properties of natalizumab in RRMS subjects...
April 11, 2017: Journal of Clinical Pharmacology
https://www.readbyqxmd.com/read/28391404/physiologically-based-pharmacokinetic-modeling-of-renally-cleared-drugs-in-pregnant-women
#16
André Dallmann, Ibrahim Ince, Juri Solodenko, Michaela Meyer, Stefan Willmann, Thomas Eissing, Georg Hempel
BACKGROUND: Since pregnant women are considerably underrepresented in clinical trials, information on optimal dosing in pregnancy is widely lacking. Physiologically based pharmacokinetic (PBPK) modeling may provide a method for predicting pharmacokinetic changes in pregnancy to guide subsequent in vivo pharmacokinetic trials in pregnant women, minimizing associated risks. OBJECTIVES: The goal of this study was to build and verify a population PBPK model that predicts the maternal pharmacokinetics of three predominantly renally cleared drugs (namely cefazolin, cefuroxime, and cefradine) at different stages of pregnancy...
April 8, 2017: Clinical Pharmacokinetics
https://www.readbyqxmd.com/read/28388353/deficiency-in-dna-damage-response-a-new-characteristic-of-cells-infected-with-latent-hiv-1
#17
Dorota Piekna-Przybylska, Gaurav Sharma, Sanjay B Maggirwar, Robert A Bambara
Viruses can interact with host cell molecules responsible for the recognition and repair of DNA lesions, resulting in dysfunctional DNA damage response (DDR). Cells with inefficient DDR are more vulnerable to therapeutic approaches that target DDR, thereby raising DNA damage to a threshold that triggers apoptosis. Here, we demonstrate that 2 Jurkat-derived cell lines with incorporated silent HIV-1 provirus show increases in DDR signaling that responds to formation of double strand DNA breaks (DSBs). We found that phosphorylation of histone H2AX on Ser139 (gamma-H2AX), a biomarker of DSBs, and phosphorylation of ATM at Ser1981, Chk2 at Thr68, and p53 at Ser15, part of signaling pathways associated with DSBs, are elevated in these cells...
April 7, 2017: Cell Cycle
https://www.readbyqxmd.com/read/28387939/parent-metabolite-pharmacokinetic-modeling-and-pharmacodynamics-of-veliparib-abt-888-a-parp-inhibitor-in-patients-with-brca-1-2-mutated-cancer-or-parp-sensitive-tumor-types
#18
Jing Niu, Christie Scheuerell, Shailly Mehrotra, Sharon Karan, Shannon Puhalla, Brian F Kiesel, Jiuping Ji, Edward Chu, Mathangi Gopalakrishnan, Vijay Ivaturi, Jogarao Gobburu, Jan H Beumer
Veliparib (ABT-888) is a novel oral poly-ADP-ribose polymerase (PARP) inhibitor that is being developed for the treatment of hematologic malignancies and solid tumors. Although the pharmacokinetics of veliparib have been studied in combination with cytotoxic agents, limited information exists regarding the pharmacokinetics (PK) of chronically dosed single-agent veliparib in patients with either BRCA 1/2-mutated cancer or PARP-sensitive tumors. The objectives of the current analysis were to characterize the population pharmacokinetics of veliparib and its primary, active metabolite, M8, and to evaluate the relationship between veliparib and M8 concentrations and poly-ADP-ribose (PAR) level observed in peripheral blood mononuclear cells (PBMCs)...
April 7, 2017: Journal of Clinical Pharmacology
https://www.readbyqxmd.com/read/28384599/the-effect-of-veno-venous-ecmo-on-the-pharmacokinetics-of-ritonavir-darunavir-tenofovir-and-lamivudine
#19
Mohamed A Ghazi Suliman, Kayode Ogungbenro, Christos Kosmidis, Alan Ashworth, Julian Barker, Anita Szabo-Barnes, Andrew Davies, Lee Feddy, Igor Fedor, Tim Hayes, Sarah Stirling, Ignacio Malagon
INTRODUCTION: To our knowledge, there is no published data on the pharmacokinetic (PK) profile of antiretroviral (ART) drugs on patients undergoing extracorporeal membrane oxygenation (ECMO) therapy. We present PK analyses of Ritonavir, Darunavir, Lamivudine and Tenofovir in a patient with HIV who required veno-venous ECMO (VV ECMO). METHODS: Plasma concentrations for Ritonavir, Darunavir, Tenofovir and Lamivudine were obtained while the patient was on ECMO following pre-emptive dose adjustments...
March 12, 2017: Journal of Critical Care
https://www.readbyqxmd.com/read/28382001/addressing-adherence-using-genotype-specific-pbpk-modeling-impact-of-drug-holidays-on-tamoxifen-and-endoxifen-plasma-levels
#20
Kristin J R Dickschen, Stefan Willmann, Georg Hempel, Michael Block
Introduction: Tamoxifen is one of the most common treatment opportunities for hormonal positive breast cancer. Despite its good tolerability, patients demonstrate decreasing adherence over years impacting on therapeutic success. PBPK modeling was applied to demonstrate the impact of drug holidays on plasma levels of tamoxifen and its active metabolite endoxifen for different CYP2D6 genotypes. Materials and Methods: A virtual study with 24,000 patients was conducted in order to investigate the development of tamoxifen steady-state kinetics in patient groups of different CYP2D6 genotypes...
2017: Frontiers in Pharmacology
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